SQ109 is a small molecule, orally active drug and is a new drug candidate in clinical development for the treatment of all forms of tuberculosis (TB), including multi-drug resistant (MDR) and extreme drug resistant (XDR) TB. SQ109 has a unique pharmacological profile, and is safe and well-tolerated in animals (90-day dosing) and humans administered a single dose up to 300 mg. SQ109 ability to kill Mtb in vitro is exactly the same for the laboratory strain or clinical isolates, regardless of drug susceptibility phenotype. This suggests that the target of SQ109 is well conserved among Mtb that cause disease. SQ109 also has remarkable synergy with both of the most important first-line antitubercular drugs, Isoniazid (INH) and Rifampin (RIF). Small amounts of SQ109 in combination with standard amounts of RIF actually made RIF-resistant clinical isolates susceptible to RIF again in vitro. In this SBIR Phase 1 application, we will explore the potential of SQ109 for treatment of MDR TB when used in combinations with first- and second-line anti-TB drugs. We will investigate two approaches: In the first approach, which is based on the remarkable synergy between SQ109 and RIF to kill Mtb in both RIFs and RIFR strains, we will evaluate whether or not we can salvage the use of RIF in treatment of RIFR strains of Mtb when combined with SQ109. In second more traditional approach, we will determine the efficacy of SQ109-based drug combinations with second-line drugs that are currently used by clinicians for treatment of patients with MDR TB. SQ109 has completed IND-directed preclinical toxicology, safety, and pharmacology studies, and a Phase 1A human safety study. In collaboration with NIAID, a Phase 1B clinical study to evaluate safety and pharmacokinetics of SQ109 administered daily for 2 weeks began in May 2009 and will conclude in March 2010. Following the successful completion of the Phase 1B trial, SQ109 will enter multinational clinical trials to evaluate efficacy of SQ109 in drug-sensitive pulmonary TB and MDR-TB. PUBLIC HEALTH RELEVANCE: SQ109 is an orally active drug and a new drug candidate in clinical development for the treatment of all forms of tuberculosis (TB), including multi-drug resistant (MDR) and extreme drug resistant (XDR) TB. TB is a contagious bacterial infection caused by Mycobacterium tuberculosis (MTB) transmitted from person to person by airborne particles. TB kills more people than any other single etiologic agent, and yet the drugs used to treat this infectious disease are so ineffective that a combination of drugs given for six months is the standard treatment regimen for uncomplicated drug-sensitive TB. The National Institute of Allergy and Infectious Diseases (NIAID) and World Health Organization (WHO) recognize TB as one of the most serious health problems in the world. Two billion (one third) of the world's population are infected with TB. The estimated incidence of TB disease was more than 9 million worldwide in 2007, and these newly identified active infections resulted in nearly 2 million deaths. WHO reports that over 450,000 of these TB cases had MDR-TB. The WHO and the U.S. FDA are encouraging pharmaceutical companies to develop new TB drugs for MDR-TB, citing the rising numbers of patients and the critical need for new effective drugs for MDR-TB. A clinical trial to establish new drug efficacy for treating MDR-TB will compare a group of MDR-TB patients treated with a standard of care dose regimen selected from the 2nd line TB drugs with a seconf group of MDR-TB patients treated with the new drug plus the same standard of care regimen used in the first group. To correctly design a new regimen for MDR-TB, the clinical trials will benefit from an understanding of how well the drugs work together in humans (pharmacokinetics, interactions) and how efficacious the new regimen is (antimicrobial efficacy of drug combinations). This study proposes to examine the interaction of SQ109 with selected 1st and 2nd line TB drugs.